Multivalent bifunctional chelator scaffolds for gallium-68 based positron emission tomography imaging probe design: Signal amplification via multivalency

Ajay N. Singh, Wei Liu, Guiyang Hao, Amit Kumar, Anjali Gupta, Orhan K. Öz, Jer Tsong Hsieh, Xiankai Sun

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ( tBu 3-1-COOH, tBu 3-2-(COOH) 2, and tBu 3-3-(COOH) 3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α vβ 3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H 31, H 32, and H 33), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α vβ 3 binding affinities (IC 50 values), enhanced specific binding was observed for multivalent conjugates (H 32: 43.9 ± 16.1 nM; H 33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H 31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga 3+ within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2, and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α vβ 3 positive PC-3 tumor xenografts (n = 3). All 68Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates ( 68Ga-3: 2.55 ± 0.50%ID/g; 68Ga-2: 1.90 ± 0.10%ID/g; 68Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.

Original languageEnglish (US)
Pages (from-to)1650-1662
Number of pages13
JournalBioconjugate Chemistry
Volume22
Issue number8
DOIs
StatePublished - Aug 17 2011

Fingerprint

Gallium
Positron emission tomography
Chelating Agents
Scaffolds
Integrins
Positron-Emission Tomography
Amplification
Imaging techniques
Tumors
Peptides
Acids
Molecular Probes
Severe Combined Immunodeficiency
Neoplasms
Molecular Imaging
Bearings (structural)
Radiopharmaceuticals
Radio
Molecular imaging
Heterografts

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Organic Chemistry
  • Pharmaceutical Science
  • Biomedical Engineering
  • Pharmacology

Cite this

@article{b34c6cc50c114795898f642f437c79e4,
title = "Multivalent bifunctional chelator scaffolds for gallium-68 based positron emission tomography imaging probe design: Signal amplification via multivalency",
abstract = "The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ( tBu 3-1-COOH, tBu 3-2-(COOH) 2, and tBu 3-3-(COOH) 3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α vβ 3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H 31, H 32, and H 33), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α vβ 3 binding affinities (IC 50 values), enhanced specific binding was observed for multivalent conjugates (H 32: 43.9 ± 16.1 nM; H 33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H 31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga 3+ within 30 min at room temperature in high radiochemical yields (>95{\%}). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2, and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α vβ 3 positive PC-3 tumor xenografts (n = 3). All 68Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates ( 68Ga-3: 2.55 ± 0.50{\%}ID/g; 68Ga-2: 1.90 ± 0.10{\%}ID/g; 68Ga-1: 1.66 ± 0.15{\%}ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.",
author = "Singh, {Ajay N.} and Wei Liu and Guiyang Hao and Amit Kumar and Anjali Gupta and {\"O}z, {Orhan K.} and Hsieh, {Jer Tsong} and Xiankai Sun",
year = "2011",
month = "8",
day = "17",
doi = "10.1021/bc200227d",
language = "English (US)",
volume = "22",
pages = "1650--1662",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Multivalent bifunctional chelator scaffolds for gallium-68 based positron emission tomography imaging probe design

T2 - Signal amplification via multivalency

AU - Singh, Ajay N.

AU - Liu, Wei

AU - Hao, Guiyang

AU - Kumar, Amit

AU - Gupta, Anjali

AU - Öz, Orhan K.

AU - Hsieh, Jer Tsong

AU - Sun, Xiankai

PY - 2011/8/17

Y1 - 2011/8/17

N2 - The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ( tBu 3-1-COOH, tBu 3-2-(COOH) 2, and tBu 3-3-(COOH) 3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α vβ 3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H 31, H 32, and H 33), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α vβ 3 binding affinities (IC 50 values), enhanced specific binding was observed for multivalent conjugates (H 32: 43.9 ± 16.1 nM; H 33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H 31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga 3+ within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2, and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α vβ 3 positive PC-3 tumor xenografts (n = 3). All 68Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates ( 68Ga-3: 2.55 ± 0.50%ID/g; 68Ga-2: 1.90 ± 0.10%ID/g; 68Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.

AB - The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ( tBu 3-1-COOH, tBu 3-2-(COOH) 2, and tBu 3-3-(COOH) 3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α vβ 3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H 31, H 32, and H 33), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α vβ 3 binding affinities (IC 50 values), enhanced specific binding was observed for multivalent conjugates (H 32: 43.9 ± 16.1 nM; H 33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H 31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga 3+ within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2, and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α vβ 3 positive PC-3 tumor xenografts (n = 3). All 68Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates ( 68Ga-3: 2.55 ± 0.50%ID/g; 68Ga-2: 1.90 ± 0.10%ID/g; 68Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.

UR - http://www.scopus.com/inward/record.url?scp=80051762411&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051762411&partnerID=8YFLogxK

U2 - 10.1021/bc200227d

DO - 10.1021/bc200227d

M3 - Article

C2 - 21740059

AN - SCOPUS:80051762411

VL - 22

SP - 1650

EP - 1662

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 8

ER -